Over 40,000 new cases of squamous cell cancer of the head and neck (SCCHN) are diagnosed in the US annually, and over 30% of these are expected to die due to incurable recurrent or metastatic disease. The role of systemic chemotherapy in this disease is only palliative, and no significant impact in patient survival has been demonstrated in the last 30 years. New therapies are clearly needed. Depsipeptide, a unique bicyclic peptide, is a potent inhibitor of the enzyme histone deacetylase (HDAC). Deregulate acetylation of histones is thought to play an important role in the pathogenesis of hematological as well as solid tumors by changing the chromatin structure and altering transcription of genes involved in cell cycle control, differentiation and apoptosis. Head and neck cancers are associated with frequent early transcriptional inactivation of tumor suppressor genes such as p16 (CDKN2A) and E-cadherin and the DNA repair genes O6-methylguanine-DNA-methyltransferase (MGMT) and hMLH1. The proposed clinical trial of depsipeptide in patients with SCCHN provides a unique opportunity to assess the anticancer activity of this drug by its novel mechanism of action of inducing gene reexpression as well as by other cytotoxic effects. In concert with this multiinstitutional NCI/CTEP sponsored clinical trial, we propose to evaluate the effects of depsipeptide exposure both on accessible tumor cells as well as normal tissues (blood and oral mucosa) with studies of histone acetylation, methylation analyses of candidate genes, cDNA microarray technology and immunohistochemical characterization of cell cycle-related proteins. Our intent is to thoroughly evaluate this novel therapy and to introduce the concept of transepithelial oral mucosa brushings as a correlate of mucosal exposure in clinical trials for patients with this disease, opening the door to possible future studies of treatment and chemoprevention.